Patients with idiopathic anaphylaxis (IA) continue to be admitted for study. The majority of the patients are admitted to the inpatient unit and undergo a history and physical examination, a blood draw for routine studies, and a bone marrow biopsy and aspirate in an attempt to elucidate the etiology and evaluate the pathogenesis of their disease. In collaboration with the NIH Clinical Center's myeloid core facility, we assess all the patient bone marrow aspirates and biopsies obtained based on the current WHO criteria to diagnose systemic mastocytosis. We are also engaged in exploring mechanisms of anaphylaxis in NSAID dependent and independent food-induced anaphylaxis. In a now completed study, we used transcriptome analysis to define patients with lipid-transfer protein-induced anaphylaxis to profile possible disturbances in gut epithelium homestasis, which may be a factor in allergic sensitization. This study highlights gene networks that may be important in IgG-induced anaphylaxis. We are evaluating alternate pathways in anaphylaxis that may be an etiology of non-IgE-mediated anaphylaxis in patients with idiopathic anaphylaxis. A study on adverse reactions to an erythropoietin peptide mimetic illustrates the importance of atypical activation of the anaphylaxis pathway. The randomized treatment protocol with omalizumab (09-I-0129) is in the patient accrual stage. Omalizumab is approved for the treatment of severe asthma and acts through a mechanism that down regulates the IgE receptor on the surface of basophils, mast cells, and dendritic cells. Omalizumab has been reported to be useful as adjunct therapy in the treatment of diseases other than asthma such as food allergy and chronic urticaria. There have been no serious adverse events to date in the study drug, in particular drug-induced anaphylaxis.